虚拟临床试验揭示靶向肿瘤相关巨噬细胞和小胶质细胞治疗胶质母细胞瘤的重要临床潜力。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Blanche Mongeon, Morgan Craig
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引用次数: 0

摘要

胶质母细胞瘤是最具侵袭性的原发性脑肿瘤,治疗后的中位生存期为15个月。标准治疗(SOC)包括切除、放疗和化疗。纳武单抗联合SOC抑制PD-1的临床试验未能提高生存率。目前缺乏对肿瘤及其免疫环境之间相互作用驱动治疗结果的定量理解。因此,我们开发了一个肿瘤生长的数学模型,该模型考虑了CD8+ T细胞、肿瘤前和抗肿瘤相关的巨噬细胞和小胶质细胞(tam)、SOC和纳武单抗。利用我们的模型,我们研究了目前正在研究的针对实体肿瘤的五种tam靶向策略。我们的研究结果表明,PD-1抑制失败是由于治疗过程中缺乏CD8+ T细胞募集,这可以用tam驱动的免疫抑制机制来解释。我们的模型预测,虽然减少TAM数量并不能改善预后,但改变它们的功能以对抗它们的原肿瘤特性有可能大大减少治疗后的肿瘤负担。特别是,通过抗cd47治疗联合SOC恢复抗肿瘤TAM的吞噬活性,预计几乎可以根除肿瘤。通过研究与抗cd47抗体Hu5F9-G4具有相同半衰期的时变功效,我们的模型预测,重复给药抗cd47可以持续控制肿瘤生长。我们认为,通过增强tam的抗肿瘤特性来靶向治疗胶质母细胞瘤是一种非常有前途的治疗方法,值得未来的临床发展。总之,我们的研究结果提供了概念证明,即机制数学建模可以揭示驱动治疗结果的机制,并探索胶质母细胞瘤等难以治疗的肿瘤的新治疗策略的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Virtual Clinical Trial Reveals Significant Clinical Potential of Targeting Tumor-Associated Macrophages and Microglia to Treat Glioblastoma.

Glioblastoma is the most aggressive primary brain tumor, with a median survival of 15 months with treatment. Standard-of-care (SOC) consists of resection, radio- and chemotherapy. Clinical trials involving PD-1 inhibition with nivolumab combined with SOC failed to increase survival. A quantitative understanding of the interactions between the tumor and its immune environment that drive treatment outcomes is currently lacking. As such, we developed a mathematical model of tumor growth that considers CD8+ T cells, pro- and antitumoral tumor-associated macrophages and microglia (TAMs), SOC, and nivolumab. Using our model, we studied five TAM-targeting strategies currently under investigation for solid tumors. Our results show that PD-1 inhibition fails due to a lack of CD8+ T cell recruitment during treatment, explained by TAM-driven immunosuppressive mechanisms. Our model predicts that while reducing TAM numbers does not improve prognosis, altering their functions to counter their protumoral properties has the potential to considerably reduce post-treatment tumor burden. In particular, restoring antitumoral TAM phagocytic activity through anti-CD47 treatment in combination with SOC was predicted to nearly eradicate the tumor. By studying time-varying efficacy with the same half-life as the anti-CD47 antibody Hu5F9-G4, our model predicts that repeated dosing of anti-CD47 provides sustained control of tumor growth. We propose that targeting TAMs by enhancing their antitumoral properties is a highly promising avenue to treat glioblastoma and warrants future clinical development. Together, our results provide proof-of-concept that mechanistic mathematical modeling can uncover the mechanisms driving treatment outcomes and explore the potential of novel treatment strategies for hard-to-treat tumors like glioblastoma.

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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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